The vertebrate renal proximal tubule is responsible for the excretory transport of a large number of potentially toxic chemicals, including, waste products of normal metabolism, drugs, environmental pollutants and drug and pollutant metabolites. These chemicals are handled by multiple, specific transport proteins that remove them from the blood and concentrate them in urine. Our research is focused on understanding control of these transporters at the cell and tissue levels. We use comparative models (single, intact proximal tubules from teleost fish, mammalian renal slices, and renal cells in culture) in combination with confocal microscopy to identify the physiologically relevant extracellular signals (hormones, metabolites, xenobiotics), and the intracellular signaling pathways that modulate xenobiotic excretion in proximal tubule. Our experiments show common signaling pathways for short-term and long-term regulation of xenobiotic export pumps. In the short-term, endothelin-1 (ET-1), acting through a basolateral, B-type ET receptor, a G-protein, nitric oxide synthase (NOS), protein kinase G (PKG) and PKC, rapidly (minutes) reduces transport mediated by the luminal ATP-driven xenobiotic export pumps, p-glycoprotein and Mrp2; although pump activity decreases, protein expression is unchanged. Importantly, three structurally unrelated classes of nephrotoxicants (radiocontrast agents, aminoglycoside antibiotics and heavy metal salts) release ET-1 from the tubules and fire the ETB receptor-NOS-cGMP-PKG-PKC signaling pathway. This appears to be an early, common event in nephrotoxicant action that links ET-1 signaling and tubular toxicity. Over the longer-term, (hours to days) sub-toxic concentrations of ET-1 and nephrotoxicants upregulate transport mediated by Mrp2 and increase the Mrp2 protein content of the epithelial cell luminal membranes. Upregulation of transport and transporter expression is abolished when signaling is blocked by inhibitors of NO synthase and PKC. Upregulation is also accompanied by increased tolerance to nephrotoxicants, suggesting selective transcriptional activation of protective pathways. Thus, short-term activation of ET signaling has long-term consequences.